Enzyme-studies will involve measurements in human colo-rectal adenocarcinomas (HCRAC) of the levels of activity (and their inhibition) of enzymes required either (a) for the salvage of precursors, or (b) for the de novo-synthesis of uridine 5'-monophosphate (UMP), and (c) for the utilization of fluorinated pyrimidines that inhibit the biosynthesis of DNA (and toxicologically that of RNA). Compounds that synergize therapeutically with (c), while diminishing their toxicity for host-tissues, will be investigated. Studies of HCRAC cells in culture permit extension of findings made with enzyme systems in vitro, and provide a logical basis for chemotherapeutic studies, not only in immune-deprived mice bearing xenografts of HCRAC, but also in such mice in which immunosuppression is maintained by treatment with anti-thymocyte sera. Among the latter, an important new development, i.e., the development of ascitic HCRAC, as well as tumors that metastasize, further encourages the development of new chemotherapeutic regimens. A new method of inhibiting the salvage of uridine and cytidine with a nucleoside that cannot enter either RNA or DNA, and the simultaneous use of a compound that preferentially inhiits the active transport of such a nucleoside into normal cells (as contrasted to neoplastic cells) will be studied in combination with inhibitors of the de novo-synthesis of UMP. Levels of normal and inhibitory nucleosides in tissues will be assessed with HPLC. Studies will be carried out of the mechanism of active transport into cells of nucleosides (and its inhibition); these will be extended to highly charged molecules, such as PALA, which apparently enter cells by diffusion, but fail efficiently to inhibit the susceptible enzyme (in the de novo-pathway). An apparently new enzyme, other than uridine-cytidine kinase, which catalyzes the phosphorylation of many nucleosides, but possibly may be absent from HCRAR, will be studied intensively.